The research training plan outlined in this application represents a proposal for funding a Mentored Clinical Scientist Development Award for an M. D. neuropathologist/scientist committed to a career studying neurological diseases. The research training activities are based on my interest in the hypothesized role of mitochondrial abnormalities in two neurodegenerative disorders, amyotrophic later sclerosis (ALS) and Huntington's disease (HD). These disease processes selectively destroy specific subsets of neurons, and oxidative damage has been implicated in the pathogeneses of both disorders. Potential mechanisms that contribute to cell degeneration include defects in oxidative phosphorylation enzymes, structural abnormalities in mitochondria of affected neurons, and mutations in the mitochondrial DNA. Using tissues from transgenic mice and humans, I plan to characterize abnormalities in specific subsets of cells and to begin to examine the roles of the possible mechanisms using histological, enzyme histochemical, immunocytochemical, ultrastructural, and molecular techniques. This effort is mad possible by a superb collection of archival human tissues from the Brain Resource Center in the Neuropathology Laboratory and because of material derived from our lines of transgenic mice, which harbor mutations in the familial ALS-linked superoxide dismutase 1 gene or expanded CAG repeats in the IT 15 HD gene. In the context of cell- specific pathology, I will examine the evolution of mitochondrial abnormalities and will correlate these findings to changes in functional measures and analyses of mitochondrial genes. Enzyme histochemical studies will determine the functional status of oxidative pathways and clarify whether affected subunits are encoded by mitochondrial or nuclear genes. pathological mutations in mitochondrial DNA will be screened for by single strand conformational polymorphism, polymerase chain reaction for known mutations, and long-range polymerase chain reaction for the entire mitochondrial DNA genome and then sequenced. FInally, cybrid cell lines will be established to analyze the pathological significance of mitochondrial abnormalities in these two disorders and in corresponding animal models. This approach working in parallel on tissues of transgenic mice and humans will be of enormous advantage in these studies. This is multidisciplinary training proposal will provide the conceptual and technical skills necessary to be an independent investigator prepared to carry out studies designed to clarify pathogeneses of neurodegenerateive disorders.